Upper body obesity (UBO) is a risk factor for non-insulin dependent diabetes mellitus (NIDDM) and coronary heart disease (CHD). In UBO but not lower body obesity (LBO) plasma triacylglycerol (TG) concentration is elevated. Although the association between hypertriglyceridemia and CHD in the general population is still controversial, hypertriglyceridemia is a risk factor for the development of pancreatitis. The aim of this proposal is to elucidate the mechanisms responsible for the increased TG concentration in UBO. We propose that (1) the increase in TG concentration in UBO results from increased hepatic FFA availability, secondary to resistance to the inhibitory effect of insulin on peripheral lipolysis, and/or decreased hepatic fatty acid oxidation, which diverts more of the hepatic FFA to esterification into VLDL-TG. These responses lead to increased hepatic VLDL-TG production and consequently increased plasma TG concentration. (2) We propose that the relative importance of these two factors (i.e. increased hepatic FFA availability and attenuated hepatic fatty acid oxidation) in the regulation of VLDL-TG production/secretion depends on the feeding status of the individual. (3) We propose that the inhibition of fatty acid oxidation in UBO results from accelerated hepatic glucose metabolism. Accelerated glucose metabolism (pyruvate production) may inhibit fatty acid oxidation by blocking FFA entry into the mitochondria. We will quantify whole body and regional (i.e. leg and splanchnic) FFA kinetics and oxidation, and VLDL-TG secretion and clearance rates in UBO and LBO individuals in the postabsorptive and postprandial state. Plasma FFA concentration will either be allowed to change, depending on the physiological state, or it will be adjusted using nicotinic acid and lipid and heparin infusion. In all studies we will use stable and radioactive isotopes and the splanchnic and leg balance techniques. Furthermore, we will use a combination of two differently labeled VLDL-TG to quantify changes in the hepatic TG pool in the postprandial state. We have preliminary data to suggest that even acute hyperglycemia may induce a temporary imbalance between TG production and secretion, thereby transiently changing the size of the hepatic TG pool(s), complicating the interpretation of the VLDL-TG measurements.